Various therapeutically active quinoline carboxamides and a method for their preparation were described in International Applications No. PCT/SE99/00676, published as WO 99/55678 and No. PCT/SE99/01270, published as WO 00/03991, which applications disclosed the utility of these compounds for the treatment of diseases resulting from autoimmunity, such as multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis and, furthermore, diseases where pathologic inflammation plays a major role, such as asthma, atherosclerosis, stroke and Alzheimer's disease.
Processes for preparing therapeutically active quinoline carboxamides also have been described in International Application No. PCT/SE2003/000780, published as WO 03/106424 and in International Application No. PCT/EP2011/061490, published as WO 2012/004338. A deuterated form of a quinoline carboxamide is described in International Application No. PCT/EP2012/061798, published as WO 2012/175541.
Pharmaceutical compositions containing a salt of a quinoline carboxamide having enhanced stability during long-term storage at room temperature, methods for the manufacture of such compositions, crystalline salts of quinoline carboxamides and methods for preparing crystalline salts of quinoline carboxamides are described in the International Application No. PCT/EP2005/050485, published as WO 2005/074899.
The use of various quinoline carboxamides for the treatment of cancer, more particularly solid cancers, such as prostate cancer and breast cancer, was disclosed in International Application No. PCT/SE00/02055, published as WO 01/30758. It has been found that these compounds bind to and inhibit the interactions of an immunomodulatory protein (S100A9), which protein promotes tumor development, influences suppressive and pro-angiogenic cells in the tumor microenvironment and participates in the establishment of pre-metastatic niches.
Tasquinimod has undergone trials for oral treatment of castrate resistant prostate cancer (CRPC) metastatic to the bone but was recently found to lack a sufficient effect on overall survival in this type of cancer.
The general term “cancer” covers a large number of malignant diseases, which may be classified in two ways: by the type of tissue in which the cancer originates (histological type) and by primary site, or the location in the body where the cancer first developed. The international standard for the classification and nomenclature of histologies is the International Classification of Diseases for Oncology, Third Edition (ICD-O-3). From a histological standpoint the cancers may be grouped into six major categories, viz. carcinoma, sarcoma, myeloma, leukemia, lymphoma and so-called mixed types.
Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a key role in immune function. In MM, collections of abnormal plasma cells accumulate in the bone marrow and interfere with the production of normal blood cells. Symptoms of MM are skeletal (bone) pain and fractures, anemia, infections, and other complications, such as polyneuropathy and renal insufficiency. MM is the second most common hematological malignancy, and still its exact causes remain unknown.
MM is normally treated using chemotherapy, which may optionally be followed by autologous stem cell transplantation (SCT).
In SCT, stem cells are removed from the patient, and are frozen and stored. Usually the patient first has undergone a high-dose chemotherapy, which destroys both healthy cells in the bone marrow and the plasma cells causing the disease, after which the removed stem cells are returned to the patient, to produce new, healthy blood cells in the bone marrow. A patient having undergone a SCT usually must take maintenance therapy for up to 2 years, e.g. with thalidomide or lenalidomide. SCT does not cure MM, it can only lead to longer survival. Furthermore, SCT can cause serious complications, especially vulnerability to infections.
MM also may be treated by chemotherapy only, in particular in patients at higher risk for complications from SCT. In that case, the chemotherapy drug often is used in combination with other drugs to reduce chemotherapy side effects, such as corticosteroids. Finally, MM also may be treated by radiation therapy.
Presently, MM is not considered curable. In 2010, less than 45% of US patients with diagnosed MM survived for more than 5 years after diagnosis, according to data from the National Cancer Institute at the National Institute of Health. It is obvious that there still remains an urgent need for new treatment options for MM.